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Essential Roles of SETD7 as Transcriptional Activator and Co-regulator of H3K36me in Cardiac Lineage Commitment

ABSTRACT: Coordinated epigenome alteration is fundamental for cardiac development. However, the precise mechanisms by which epigenetic modifying enzymes regulate cardiac development are still unclear. Here we identify SET domain containing protein 7 (SETD7) as a key regulator of cardiac differentiation. ChIP-seq reveals that SETD7 has distinct groups of target genes and regulates its stage-specific expression during cardiomyocyte differentiation, which is crucial for lineage commitment. We find SETD7 associates with stage-specific co-factors, such as SWI/SNF chromatin remodeling factors during mesodermal formation and transcription factor NKX2-5 in cardiac progenitor differentiation. Cross-analysis of epigenetic modifications shows that SETD7 recognizes and binds with active histone marker H3K36 methylation on gene-body region of its target genes. We further demonstrate SETD7 is required for functional properties of terminally differentiated cardiomyocytes. Together, our results suggest unidentified roles of SETD7 in cardiac lineage commitment and provide new insights into the crosstalk between epigenetic dynamics and epigenetic modifying enzymes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE107785 | GEO | 2018/04/17

REPOSITORIES: GEO

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Essential Roles of SETD7 as Transcriptional Activator and Co-regulator of H3K36me in Cardiac Lineage Commitment

Project description:Essential Roles of SETD7 as Transcriptional Activator and Co-regulator of H3K36me in Cardiac Lineage Commitment

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SETD7 functions as a transcription repressor in prostate cancer via methylating FOXA1 [ChIP-seq]

Project description:We recently reported that in prostate cancer LSD1 can demethylate the lysine 270 of FOXA1 to stabilize FOXA1 chromatin binding and thus can enhance the activities of AR and other transcription factors that require FOXA1 as a pioneer factor. However, the methyltransferase that can methylate FOXA1 and negatively regulate the LSD1-FOXA1 oncogenic axis remains unknown. SETD7 is initially identified as a transcriptional activator through methylating histone 3 lysine 4 but can also function as a methyltransferase on other non-histone substrates. However, its function in PCa remains poorly understood. In this study, we found that SETD7 confers tumor suppressor activity in PCa cells and that loss of SETD7 expression is significantly associated with PCa progression and tumor aggressiveness. Mechanistically, we found that SETD7 primarily acts as a transcriptional repressor in CRPC cells by functioning as a methyltransferase of FOXA1-K270 to disrupt FOXA1-mediated transcription. Overall, our study provides novel mechanistic insights into the tumor-suppressive and transcriptional repression activities of SETD7 in mediating PCa progression and therapy resistance.

2023-08-23 | GSE218092 | GEO

SETD7 promotes lateral plate mesoderm formation by modulating the Wnt/b-catenin signaling pathway

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Essential and unexpected role of YY1 to promote mesodermal cardiac differentiation

Project description:Rationale: Cardiogenesis is regulated by a complex interplay between transcription factors and chromatin-modifying enzymes. However, little is known about how these interactions regulate the transition from mesodermal precursors to cardiac progenitor cells (CPCs). Objective: To identify novel regulators of mesodermal cardiac lineage commitment. Methods and Results: We performed a bioinformatic-based transcription factor-binding site analysis on upstream promoter regions of genes that are enriched in ES cell-derived CPCs. From 32 candidate transcription factors screened, we found that YY1, a repressor of sarcomeric gene expression, is present in CPCs in vivo. Interestingly, we uncovered the ability of YY1 to transcriptionally activate Nkx2.5, a key marker of early cardiogenic commitment. YY1 regulates Nkx2.5 expression via a 2.1 kb cardiac-specific enhancer as demonstrated by in vitro luciferase-based assays and in vivo chromatin immunoprecipitation (ChIP) and genome-wide sequencing analysis. Furthermore, the ability of YY1 to activate Nkx2.5 expression depends on its cooperative interaction with GATA4 at a nearby chromatin. Cardiac mesoderm-specific loss-of-function of YY1 resulted in early embryonic lethality. This was corroborated in vitro by ES cell-based assays where we show that the over-expression of YY1 enhanced the cardiogenic differentiation ES cells into CPCs in a cell autonomous manner. Conclusion: These results demonstrate an essential and unexpected role for YY1 to promote cardiogenesis as a transcriptional activator of Nkx2.5 and other CPC-enriched genes. We report the identification of putative YY1 target genes in cardiac progenitor cells (CPCs). Two samples of independently FACS-purified eGFP+ CPCs were examined against the input.

2013-06-01 | E-GEOD-35370 | biostudies-arrayexpress

SETD7 functions as a transcription repressor in prostate cancer via methylating FOXA1 [RNA-seq]

Project description:To determine the transcriptional impact of SETD7,MLL1 silencing in CRPC cells, we performed an RNA-seq analysis in those 22Rv1 stable cell lines (under hormone-depleted conditions)

2023-08-23 | GSE218093 | GEO

1H NMR metabolite monitoring during the differentiation of human induced pluripotent stem cells provides new insights into the molecular events that regulate embryonic chondrogenesis

Project description:The integration of cell metabolism with signalling pathways, transcription factor networks and epigenetic mediators is critical in coordinating molecular and cellular events during embryogenesis. Induced pluripotent stem cells (IPSCs) are an established model for embryogenesis, germ layer specification and cell lineage differentiation, advancing the study of human embryonic development and the translation of innovations in drug discovery, disease modelling and cell-based therapies. The metabolic regulation of IPSC pluripotency is mediated by balancing glycolysis and oxidative phosphorylation, but there is a paucity of data regarding the influence of individual metabolite changes during cell lineage differentiation. We used <sup>1</sup>H NMR metabolite fingerprinting and footprinting to monitor metabolite levels as IPSCs are directed in a three-stage protocol through primitive streak/mesendoderm, mesoderm and chondrogenic populations. Metabolite changes were associated with central metabolism, with aerobic glycolysis predominant in IPSC, elevated oxidative phosphorylation during differentiation and fatty acid oxidation and ketone body use in chondrogenic cells. Metabolites were also implicated in the epigenetic regulation of pluripotency, cell signalling and biosynthetic pathways. Our results show that <sup>1</sup>H NMR metabolomics is an effective tool for monitoring metabolite changes during the differentiation of pluripotent cells with implications on optimising media and environmental parameters for the study of embryogenesis and translational applications.

2023-05-24 | MTBLS4854 | MetaboLights

Braveheart is a long non-coding RNA necessary for cardiac lineage commitment

Project description:Purpose: Long non-coding RNAs (lncRNAs) display development-specific gene expression patterns, yet we know little about their precise roles in lineage commitment. Here, we discover a novel mammalian heart-associated lncRNA, AK143260, necessary for cardiac lineage specification. Methods: Gene expression profiles of mouse ESCs and differentiated organs were analyzed for master regulators of lineage commitment. The AK143260 transcript was shown to be strongly expressed in mESCs and in cells undergoing cardiac differentiation. Its role in cardiac differentiation was examined using depletion and in vitro differentiation systems, with morphological and gene expression profiling at different time-points. Results: mESCs depleted of AK143260, named Braveheart, fail to differentiate into cardiomyocytes and to activate a core cardiac gene regulatory network including key transcription factors driving cardiogenesis. We show that Braveheart functions upstream of MesP1 (mesoderm posterior 1), a transcription factor critical for specification of the earliest known multi-potent cardiovascular progenitor and in promoting epithelial-mesenchymal transition (EMT). Consistent with this, Braveheart depletion leads to morphological defects and loss of cardiogenic potential in a defined in vitro cardiomyocyte differentiation system. Furthermore, Braveheart is necessary to maintain myocardial gene expression and myofibril organization in neonatal cardiomyocytes. Conclusions: These findings reveal that Braveheart is an important regulator of cardiac commitment and implicate lncRNAs as potential therapeutic targets for cardiac disease and regeneration. Gene expression profiles from control and Bravheart-depleted mESCs were obtained by RNA-Seq on an Illumina HiSeq2000 instruments at Days 0,3,6 and 9. Gene expression profiles from mESCs, MEFs, partially reprogrammed MEFs and miPS cells were obtained by RNA-Seq on Illumina GAII/GAIIx instruments.

2013-01-30 | E-GEOD-39656 | biostudies-arrayexpress

Genome-wide maps of epigenetic features in G1E model and in mouse primary erythroblasts.

Project description:Interplays among lineage specific nuclear proteins, chromatin modifying enzymes and the basal transcription machinery govern cellular differentiation, but their dynamics of actions and coordination with transcriptional control are not fully understood. Alterations in chromatin structure appear to establish a permissive state for gene activation at some loci but they play an integral role in activation at other loci. To determine the predominant roles of chromatin states and factor occupancy in directing gene regulation during differentiation, we mapped chromatin accessibility, histone modifications, and nuclear factor occupancy genome-wide during mouse erythroid differentiation dependent on the master regulatory transcription factor GATA1. Remarkably, despite extensive changes in gene expression, the chromatin state profiles (proportions of a gene in a chromatin state dominated by activating or repressive histone modifications) and accessibility remain largely unchanged during GATA1-induced erythroid differentiation. In contrast, gene induction and repression are strongly associated with changes in patterns of transcription factor occupancy. Our results indicate that during erythroid differentiation, the broad features of chromatin states are established at the stage of lineage commitment, largely independently of GATA1. These determine permissiveness for expression, with subsequent induction or repression mediated by distinctive combinations of transcription factors. Using ChIP-Seq technology to examine DNase hypersensitivity, three transcription factors, and four histone modifications in Gata1-null murine G1E line and rescued G1E-ER4 subline, and also two of the transcription factors in mouse primary erythroblasts. ChIP input DNA was sequenced in each cell type as controls.

2011-07-05 | E-GEOD-30142 | biostudies-arrayexpress

Essential and unexpected role of YY1 to promote mesodermal cardiac differentiation

2013-06-01 | GSE35370 | GEO

A mass spectrometry survey of chromatin-associated proteins in pluripotency and early lineage commitment

Project description:Pluripotent Embryonic Stem Cells (ESCs) can be captured in vitro in different states, ranging from unrestricted ‘naïve’ to more developmentally constrained ‘primed’ pluripotency. Complexes involved in epigenetic regulation and key transcription factors have been shown to be involved in specifying these distinct states. In this study, we use proteomic profiling of the chromatin landscape in naive pluripotent ESCs, Epistem cells (EpiSCs) and early differentiated ESCs to survey the chromatin in naïve and primed pluripotency and during differentiation. We provide a comprehensive overview of epigenetic complexes situated on the chromatin and identify proteins associated with the maintenance and loss of pluripotency. The findings presented here indicate major compositional alterations of epigenetic complexes starting from ESC priming onwards. Our results contribute to the understanding of ESC differentiation and provide a framework for future studies of lineage commitment of ESCs.

2019-07-04 | PXD011782 | Pride

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